Transcript AWOtherapeutics

DRUG THERAPY OF AIRFLOW OBSTRUCTION
PROFESSOR B J LIPWORTH
• Preventers (anti-inflammatory)
• Relievers (bronchodilators)
THE INFLAMMATORY CASCADE
Genetic predisposition + Trigger factor
(e.g. viral, allergen, chemicals)
Airway inflammation
Mediators
(e.g. histamine, leukotriene)
Twitchy smooth muscle
(Hyper-reactivity)
• Avoidance
• Anti-inflammatory
- corticosteroid
• Anti-leukotriene
Anti-histamine
• Bronchodilators
- 2-agonists
THE ASTHMA TREATMENT PYRAMID
Oral
Steroid
Controller
(Additive to ICS )
Preventer
Reliever
Theophylline
Leukotriene-antagonist
Long-acting 2-agonist
Inhaled steroid
( Cromogylcate ?)
Short-acting 2-agonist PRN
Increasing
severity
BTS Asthma Guidelines
Step 4
Step 3
Step 1
intermittent
Step 2
mild
persistent
moderate
persistent
severe
persistent
Short-acting ß2 agonists prn
Inhaled steroids
Add on LABA
Add on LTRA/Theo
ANTI-INFLAMMATORY: CORTICOSTEROIDS
• Used in asthma and COPD
• Oral steroid (prednisolone) - low therapeutic ratio
- only used for acute exacerbations
• Inhaled steroid (beclomethasone) - higher therapeutic ratio
- used for maintenance therapy
• Optimise lung delivery - large volume spacer
Lung deposition of
HFA-BDP, fluticasone and CFC-BDP
MMAD = 1.1 µm
MMAD = 2.5 µm
MMAD = 3.5 µm
Actions of a spacer device
• Avoids coordination problems with pMDI
• Reduces oropharyngeal and laryngeal side effects
• Reduces systemic absorption from swallowed
fraction
• Acts a holding chamber for aerosol
• Reduces particle size and velocity
• Improves lung deposition
ANTI-INFLAMMATORY: CROMONES
• Only used in asthma (eg Cromoglycate)
• Mast cell stabiliser - weak anti-inflammatory cf steroids
• Cromoglycate effective in atopic children (exercise asthma)
• Inhaled route only (compliance with QID dosing )
• No longer used due to poor efficacy
ANTI-INFLAMMATORY: LEUKOTRIENE RECEPTOR ANTAGONISTS
• Only used in asthma: bronchodilator + anti-inflammatory
• Montelukast - oral route,once daily, high therapeutic ratio
• Less potent anti-inflammatory than inhaled steroid
• 2nd line: complimenatary non steroidal ant-inflammatory
additive to inhaled steroid
• Effective in exercise induced asthma
• Also effective in allergic rhinitis ( with anti-histamine )
ANTI-INFLAMMATORY: ANTIHISTAMINES
• H1 receptor antagonists
• Oral route
• Only of value when known allergenic trigger
(e.g. HDM ,pollen or cat) -ie in atopic asthma
• 1st generation :Chlorpheniramine-sedative
• 2nd generation: Cetirizine,Loratadine-non sedative
• 3rd generation: Levocetirizine,Desloratadine - non sedative
• More effective in allergic rhinitis than asthma
• Additive effects when given together with leukotreine
antagonist
ANTI-INFLMMATORY
Anti-IgE
• Anti-IgE monoclonal antibody : Omalizumab (Xolair)
• Omalizumab inhibits the binding to the high-affinity
IgE receptor and inhibit mediator release from
basophils and mast cells .
• Injection every 2-4 weeks .
• For patients with severe persistent allergic asthma
despite max therapy –ie step 5 .
• Very expensive .
• No effect on pulmonary function but reduces
exacerbations .
BRONCHODILATORS: 2-AGONISTS
Stimulate bronchial smooth muscle 2-receptors:  cAMP
Short-acting - salbutamol
Long-acting – salmeterol / formoterol
Combination inhalers-eg Seretide / Symbicort
Used in asthma and COPD
High therapeutic ratio when given by inhaled route
Systemic 2 effects when given systemically or at high inhaled
doses
• High nebulised doses given in acute attack
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Muscarinic (cholinergic) receptors
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M1-receptors enhance the
cholinergic reflex
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M2-receptors inhibit
acetylcholine release
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M3-receptors mediate
bronchoconstriction and
mucus secretion
BRONCHODILATORS: ANTICHOLINERGICS
• Block post junctional end plate M3 receptors
• Ipratropium qid , Tiotropium od
- inhaled route only - high therapeutic ratio
• Used in COPD - less effective in asthma
• High nebulised doses of ipratropium used in acute COPD
and in acute asthma
BRONCHODILATOR/ANTINFLAMMATORY
:METHYLXANTHINES
• Oral (Theophylline) for maintenance therapy
• SR formulation useful for nocturnal dips
• Used as add to inhaled steroid as complimentary non
steroidal anti-inflammatory
• IV (Aminophylline) for acute attacks
• Non selective phosphodiesterase inhibitor (cAMP)
• Adenosine antagonist
• Low therapeutic ratio - P450 drug interactions (e.g.
erythromycin)
• Used in asthma and COPD
Anti-inflammatory :PDE4 inhibitors
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Roflumilast –oral tablet od
Indicated for COPD only
Minimal effect on FEV1
Reduces exacerbations –additive to LABA or LAMA
Adverse effects : Nausea/Diarrhoea/Headache/Weight
loss
• ? Place in COPD guidelines as add on to
ICS/LABA/LAMA
Mucolytics
• Oral carbocisteine , erdosteine
• To reduce sputum viscosity and aide sputum
expectoration [and reduce exacerbations ] in
COPD
• Rarely used –only as add on to other treatments
TREATMENT OF CHRONIC ASTHMA
• AIMS: Abolish sympt, min 2-use, normalise FEV1, reduce PEF
variability, reduce exac, prevent long term airway remod
• Avoid triggers
• Suppress inflammatory cascade with inh steroid
+/- non steroidal anti-inflamm therapy –eg theophylline ,antileukotriene ,anti-histamine
• Stabilise smooth muscle with LABA –only once optimal antiinflamm therapy in place
TREATMENT OF ACUTE ASTHMA
• Oral prednisolone (or iv hydrocortisone )
• Nebulised high dose salbutamol, ± Neb ipratropium, ± iv
aminophylline/magnesium
• 60% O2
• ITU Assisted mecahnical intubated ventilation if falling
PaO2 and rising PaCO2
- never use respiratory stimulant
Non-pharmacological intervention:
smoking cessation
Never smoked
or not susceptible
to smoke
FEV1 (% of value at age 25)
100
75
Smoked regularly
and susceptible
to its effects
Stopped at 45
50
Disability
25
Stopped at 65
Death
0
25
50
Age (years)
75
Fletcher et al., 1977
TREATMENT OF STABLE COPD
• Prevent FEV1 decline - stop smoking
• Treat reversible component
- Inhaled steroid
- Short/Long acting beta-2 agonists
- Short/Long acting anticholinergics
-Theophylline
• Pulm rehab
• Vaccination –influenza/pneumococcal
• Domiciliary O2 to prevent cor pulmonale
• Venesection for polycythaemia
• Lung volume reduction surgery for highly slected patients
TREATMENT OF ACUTE COPD
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Nebulised high dose salbutamol + ipratropium
Oral prednisolone
Antibiotic (amoxycillin) if infection
24-28% O2
Respiratory stimulant (doxapram) to improve ventilation
Non invasive ventilation instead of doxapram
ITU Intubated assisted ventilation only if reversible
component (eg pneumonia)